1,2,4-oxadiazine-3,6-diones

ABSTRACT

1, 2, 4-OXADIAZINE-ONES, USEFUL AS ALGICIDES, BACTERICIDES AND FUNGICIDES, ARE OBTAINED BY REACTING AN N-hydroxy-urea and a dihalogenated organic derivative having halogen atoms on two adjacent carbon atoms.

United States Patent Makula et al.

[ l,2,4-OXADIAZINE-3,6-DIONES [72] Inventors: Daniel Makula; Monique Druet, both of Lyon; Batriee Gonthier,

Caluire, all of France [73] Assignee: Progie, Paris, France [22] Filed: April 1, 1970 [21] Appl. No.: 24,859

[30] Foreign Application Priority-Data April 3, 1969 France ..6909530 [56] References Cited UNITED STATES PATENTS 1 1 Oct. 3, 1972 Bernstein et al. ..260/244 R FOREIGN PATENTS OR APPLICATIONS 1,432,738 2/1966 France ..260/244 R 1,184,071 3/1970 Great Britain ..260/244 R OTHER PUBLICATIONS Hard at al. J. Amer. Chem. Soc. Vol. 77, Pages 5359- 5364 (i955).

Primary Examiner-Natalie Trousof =Attarney-Browdy and Neimark 57 ABSTRACT 1, 2, 4-oxadiazine-ones, useful as algicides, bactericides and fungicides, are obtained by reacting an N- hydroxy-urea and a dihalogenated organic derivative having halogen atoms on two adjacent carbon atoms.

12 Claims, No Drawings ketone groups either in the -position or in the 3 and 5- positions.

New 1,2,4-oxadiazine-ones have now been provided which answer the general formula:

in which X and Y, identicalor difierent, represent the 0 R v --function or the-lH-group in which R is hydrogen or CH;,, with the exception of the compounds in which X is equal to R and R identical or different, indicate a C to C alkyl residue or a phenyl radical having possibly one or several substituents chosen among halogens, and nitro, C, alkyl, C 3 alkoxy, trifiuoromethyl groups.

Hence the compounds of Formula (I) may be perhydro-l, 2,4-oxadiazine-3-ones; 3,6-diones and 3,5,6- triones. Under ambient conditions they are usually present in the form of white or slightly colored crystalline solids, usually soluble in common solvents, although some of them are oils.

The heterocycles of Formula (I) are produced, in a general way, by reacting, in the presence of a base, a conveniently substituted N-hydroxy-urea with a dihalogenated organic derivative having the halogen atoms on two adjacent carbons. It is possible to indicate, without limiting the invention field by theoretical explanations about reaction mechanism, that there occurs first a condensation of the dihalogenated derivative and hydroxy-urea, giving an O-substituted urea; then a cyclization of this intermediary product, which leads to the heterocycle. Each of these occur with the removal of an halogen atom. The total reaction may be schematized as follows:

The N-hydroxy-ureas (b) used as raw materials areknown type products, which may be obtained accord-' ing to the usual techniques, for example by reaction of an N substituted hydroxyl-amine with the convenient 2 isocya rate. It is easily understood, with regard to Formula (I) hereinabove, that the dihalogenated derivatives (2) used in the process according to the invention may be, respectively, according to the desired final 5 product, a l,2-dihalogeno-ethane; 1,2-dihalogenopropane; 2,3-dihalogeno-butane; halogeno-acetyl halide; a-halogeno-propionyl halide; oxalyl halide.

There are used quantities of reagents corresponding at least to stoichiometry. But, in order to obtain a more complete reaction and to avoid the formation of byproducts such as diureas, it is better to operate with an excess of dihalogenated derivative, with regard to N- hydroxy-urea quantity, the same as possibly with a base excess. Reaction is advantageously achieved .in the presence of an organic solvent inert is the operative conditions. I

The general process according to the invention has variants, according to the nature of the used 2O dihalogenated reagent. When this reagent is an hydrocarbon derivative, which leads to the obtaining of a monoketonic heterocycle, there is generally used as a base, an alkali metal hydroxide, which is advantageously introduced into the reaction mixture as an aqueous solution. When using an acyl halide as a dihalogenated reagent, to obtain di-or triketonic heterocycles, use of an alkaline solution must be avoided as it would give rise to hydrolysis of the acyl halide. So, it is convenient, in this latter case, to substitute for alkaline hydroxides, a tertiary organic base,

for fixing hydrogen halides, as for example triethylamine or pyridine. If acyl halide has only a radical Hal CO-, the reaction may be achieved in two stages: in the first stage, during which acyl halide is present in free state, the reaction is operated in the presence of a ,tertiary organic base; in the second stage, that is when the CO group of said acyl halide is linked to the initial urea, it is possible to use again an alkaline solution in order to achieve cyclization.

In the same way, the organic solvent which may be used in the process varies with regard to the peculiar dihalogenated derivative. If it is an hydrocarbon derivative 'it is possible to choose the solvent from among aliphatic alcohols such as methanol or ethanol, aromatic hydrocarbons such as benzene, toluene, xylene, etc...If it is an acyl halide, the use of alcohols which would not be inert in operative conditions must be avoided and aromatic hydrocarbons are used or '50 ketones, such as acetone, etc. Once the reaction has alkali metal hydroxide, filtration is not obligatory.

However it may be useful, as it permits removal, in case of need, of the diurea which could have been formed asa secondary product. Then it is possible to wash the filtrate with an alkaline solution in order to remove fromit any trace of non-transformed initial N-hydroxy-urea. Then the desired heterocycle is isolated by methods of known type, as for example by precipitation with water of oxadiazine-one or solvent evaporation. In this last 5 case, the operation is followed with a water-washing,

when reaction has been achieved in the presence of an alkaline hydroxide in order to remove the alkali metal halide formed during reaction. The final product may at last be recrystallized out of W as an alcohol, as methanol or ethanol, a chlorinated aliphatic hydrocarbon such as chloroform, an aromatic hydro-carbon such as benzene or a mixture of alcohol and water, or of ketone and water.

Formula (1) compounds according to the invention possess interesting biocidal properties. Taken individually, they have been shown to be efficient, either separately, or the most generally, simultaneously, for combatting bacterian and fungic degradations the same as for destroying or inhibiting algae growth. Moreover some of those bodies are nematocides. Besides, their pesticidal interest is increased by the fact that they are little toxic with regard to fishes and mammals. So, for example, ichthyotoxicity, studied on trouts, of 2-methyl 4- (3,4-dichlorophenyl) perhydro-l,2,4-oxadiazine- 3,6-dione is non-existent at theamount of p.p.m. (parts per million) in water, in a 3 hour test. The LD 50 of this heterocycle (lethal amount corresponding to a 50 percent death-rate of the animals submitted to the test), studied on mice, is about 650 mg/kg. LD 50 of 4-, methyl-2 phenyl perhydro-l ,2,4-oxadiazine-3-one is greater than 1,000 mg/kg.

The polyvalent activity of several of those compounds makes those ones quite useful for some applications, for example, for water treatment, and especially of industrial water circuits, (simultaneous fight against algae, bacteria, fungi) or for the protection of materials such as for example, glues (simultaneous fight against bacteria, fungi). As fungicides they are especially interesting for the protection of cellulosic materials such as wood, or textile fabrics and fibers, resins and elastomers, paints, varnishes, etc.

The compounds according to the invention are usa-' ble, as biocidal agents, as such or according to the usual formulations, with regard to contemplated uses. For example, they may be incorporated such as they are in the material to be treated, the solid products being previously only ground. They may also be applied by spraying or aspersion, in the form of liquid compositions, such as in aqueous suspensions or emulsions, organic or hydro-organic solutions. In those last cases, it is possible to use as solvents, classical products such as hydrocarbons, for example toluene, xylene, petroleum cuts, alcohols, ketones for example acetone, methylisobutylketone, etc.

Moreover the compositions based on those active materials may contain various adjuvants such as solubilizing, dispersing, wetting, fixing, stabilizing agents, for example alkali pyrophosphates, soya lecithin, alkali metal lignosulfonates, carboxymethylcellulose, polyvinylic alcohol etc. Besides they may contain other biocides of known type.

The examples hereinafter illustrate the object of the invention. Examples 1 to 3 relate to the manufacture of heterocycles according to the invention. The following examples emphasize their biocidal activity.

EXAMPLE 1 In a flask provided with a central stirring and an ascending cooler, 140 gm. (0.75 mole) or 1,2-dibromo ethane and 500 ml of ethanol were boiled under reflux; then in about 1% h. there was added a solution of 40 gm. of sodium hydroxide (1 mole) in 250 ml. of water,

containing 1 18 gm. (0.5 mole) of N-3,4-dichloro-phenylN-methyl N '-hydroxy-urea. Reflux was maintained during 2 hours after addition ended. Then the slightly cloudy solution was hot-filtered. After cooling, 1 liter of ice-water was added to the filtrate. The formed precipitate was separated by filtration and recrystallized out of chloroform. There was obtained 94 gm. of a white solid (yield 72 percent with regard to theory) melting at 91C.

The chemical analysis has given the following results:

N C H Cl Found 10.54 46.28 3.96 27.05 Calculated 10.83 46.0 3.87 27.]

Mass spectrometry and nuclear magnetic resonance indicate that the structure of the obtained white solid corresponded to 2-methyl 4-( 3,4-di-chlorophenyl )-perhydro-1,2,4-oxadiazine 3-one (product No. 1).

In operating in the same conditions as hereinabove,

from convenient raw materials there was prepared series of perhydro-l ,2,4oxadiazine 3-ones of Formula (I) the substituents R, and R and the physical characteristics of which are given in the Table l hereinafter (for those compounds, X Y CH TABLE 1 I Melting Product n R R; point 2 CH 7476 C.

4 CHa- 77 C.

CHa-

5 CHa ()1 116 C.

i Cl 6 CgHs- 84( 7 Czllr- 01 68 C. 14 -CH--- (3113- 85 CH; C} 01 CR3 9 N'C3H7 Oil Q 15. \g O1 EXAMPLE 3 in a flask provided with a central stirring there was 20 introduced 236 g. (1 mole) of N-3,4-dichlorophenyl EXAMPLEZ N'methyl -N'hydroxy urea and 140 gr. (1.1 mole) of 1 alyl chloride in solution in 2 500 ml of anhydrous In a flask rovlded with a central stlrrin there was OX 0 introduced 2%6 gm. (1 mole) of N- 3 4-dicl loro phenyl acetone then at a temperature exceeding 10 N-methyl-N'-hydroxy urea and 125 (1.1 mole) OF 202 (2 moles) of methyl anlme was slowly added monochloroacetyl chloride in solution in 2,500 ml. of and after 1 hour h formed amme hydrochloride was anhydrous acetone; then there was added S1 owly at a removed by filtration. Ice water was added to the filtemperature not exceeding 10C, 101 gr. (1 mole of Hate formed F' Separated and triethybaminel After half an hour, the amine recrystallized out of a mixture of acetone/water. There hydrochloride formed was removed by filtration. Then, obtamed ofa whlt? sohd meltmg at 142 at the temperature of 20C, an aqueous solution conwhlch: by ana'lyss has shown be 2'meth y] taining 40 gt (1 mole) of sodium hydroxide was v(3,4-d1chlorophenyl) l,2,4-oxadlazlne-3,5,6-trlonepoured slowly into the filtrate. The reaction mixture (product first was neutral, suddenly became At 4 this time, ice water was added to the mixture, the formed precipitate re v d b filtr ti d 35 Solutions of various heterocycles of the previous exrecrystallized from toluene. 205 g. of a white solid pl were p p y first dissolving the he erocymelting at 122C. was obtained. Mass spectrometry has cles 1n a polyalcohol ether known under the name of shown that this product structure corresponded to 2- Polyglycol 400" (that is the condensation product of methyl 4-(3, 4-dichloro-phenyl') perhydro-l,2,4-oxethylene oxide on one mole water, having a mean adiazine 3,6-dione (product No. 10 molecular weight or 400 then by diluting the solution Operating in the same conditions as above, starting in water in order to obtain concentrations of active infrom other hydroxy-ureas, there were obtained other gredient varying between 1 and 50 p.p.m. Then those l,2,4-oxadiazine-3,6-diones of Formula (I) with Y solutions were sown with suspensions of a mixture of CO, the structure and melting point of which are given unicellular green algae in which there was above all the in the following Table 2. species Scenedesmus crassus; then nutritive extracts were added to the obtained compositions and every TABLE 2 sample was placed in artificial light for 12 or 24 hours Melting at 25C, during 8 days. 55 X Thereafter either algae development or the absence of development or still a partial development (i) were evaluated. The obtained results are si fi ill b kihsrsinafiereno--.

TABLE 3 n CH2- CH3 Nor- 201 Active Ingredient Amounts Algicidal H Product No in p.p.m. Activity 12 CH CH: 108 l i C1 S Q so 4 1 u 1 10 z 50 10 l i l0 ol J3 so l3 c1r cm- 16 l 01- s CH3 EXAMPLE 5 Product 10 of Example 2 was introduced, in various amounts, into a nutritive mixture which was sown with bacterium Staphylococcus aureus. The mixture was incubated at optimal conditions during a time normally sufficient for bacteria development. This test provided determination of the minimal amount at which this product could be considered as being bacteriostatic. In order to know if it was also a bactericide, an aliquot part from the previous test was then introduced into a new nutritive mixture. Then, an absence of development of the active product for a determined amount corresponded to the death of all the present bacteria. The results of those bactericidal and bacteriostatic tests are given in Table 4, hereinafter, in which is indicated either bacterium development or the absence of development or a partial development (i).

TABLE 4 Amounts Efficiency (p.p.m.) Bacteriostatic Bactericidal EXAMPLE 6 TABLE 5 Stocks Efficiency with regard to the amounts active ingredient s/ Product No.

110" 5.10" 1.10 5.10" 1.10- Polystictus verricalar W T '2" 6 z 10 t 14 I Caniophora puteana z t 3 z 4 z 6 z z 10 z 14 1- Gyrophana lacrymans 3 :t i 4 :r; a:

6 x l 1 :t. [4 :t

in which R is hydrogen or CH R is alkyl of one to five carbon atoms or phenyl; and R is alkyl of one to five carbon atoms, phenyl, phenyl mono-, di-, or tri-substituted with halogen, nitro, alkyl of one to three carbon atoms, or alkoxy of one to three carbon atoms or phenyl mono-substituted with trifuloromethyl.

2. An oxadiazine-dione according to claim 1 wherein R is CH 3. An oxadiazine-dione according to claim 2 wherein R is hydrogen.

4. An oxadiazine-dione according to claim 2 wherein R is methyl.

5. An oxadiazine-dione according to claim 3 wherein R is 6. An oxadiazine-dione according to claim 4 wherein R2 is 8. Oxadiazine-dione according to claim 3 wherein R 9. Oxadiazine-dionc according to claim 4 wherein R 

2. An oxadiazine-dione according to claim 1 wherein R1 is CH3.
 3. An oxadiazine-dione according to claim 2 wherein R is hydrogen.
 4. An oxadiazine-dione according to claim 2 wherein R is methyl.
 5. An oxadiazine-dione according to claim 3 wherein R2 is
 6. An oxadiazine-dione according to claim 4 wherein R2 is
 7. Oxadiazine-dione according to claim 3 wherein R2 is
 8. Oxadiazine-dione according to claim 3 wherein R2 is
 9. Oxadiazine-dione according to claim 4 wherein R2 is
 10. Oxadiazine-dione according to claim 4 wherein R2 is
 11. Oxadiazine-dione according to claim 4 wherein R2 is
 12. Oxadiazine-dione according to claim 4 wherein R2 is 